# Structural insights into zinc homeostasis

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $65,994

## Abstract

Project Summary / Abstract
The Zrt-, Irt-like Protein (ZIP, or Solute Carrier 39 (SLC39)) family of membrane proteins mediate zinc influx1.
Zinc homeostasis is a critical regulator of a variety of physiological processes, including immune function, insulin
secretion, and cell communication, and plays key roles in protein structure and catalysis2. Because both excess
and deficient zinc levels are cytotoxic, zinc homeostasis is tightly controlled in mammalian cells via an abundant
network of membrane proteins that act as zinc importers (ZIP / SLC39 family) or zinc exporters (ZnT / SLC30
family). Zinc homeostasis proteins are potential pharmacological targets in neurodegenerative disorders and
cancer, but progress is hampered by a lack of structural and mechanistic information. No full length mammalian
structures of ZIP family members have been solved and no in vitro functional assays exist. ZIP9 (SLC39A9)
represents a novel treatment avenue for prostate cancer3. The prostate has the highest concentration of zinc in
the body, which promotes apoptosis and helps maintain low levels of cellular proliferation. In prostate cancer,
zinc levels decrease, leading to tumor proliferation4. Prostate zinc levels cannot be rescued with dietary
supplements5,6. Recently, ZIP9 was identified as a membrane Androgen Receptor (mAR) which mediates
testosterone-induced apoptosis7. ZIP9 is upregulated in prostate cancer, but to realize its potential as a
pharmacological target a full structural and functional characterization is required. My objective is to elucidate
the structure and mechanism of ZIP9. Aim 1 is to develop a proteoliposome-based functional assay using
stopped-flow fluorescence spectroscopy and site-directed mutagenesis to characterize the mechanism of ZIP9.
Aim 2 is to determine the structural basis of zinc influx by ZIP9 using Microcrystal Electron Diffraction (MicroED).
Aim 3 is to examine ZIP9's mAR characteristics by determining the molecular and structural basis of its
interactions with testosterone and G proteins using biochemistry and high resolution single particle cryogenic
electron microscopy (cryoEM). This research will unravel the mechanism of ZIP-mediated Zn2+ influx and clarify
ZIP9's putative role as a membrane Androgen Receptor, broadening our understanding of zinc homeostasis and
paving the way for the use of ZIPs as a pharmacological target in prostate cancer and beyond.

## Key facts

- **NIH application ID:** 10315746
- **Project number:** 1F32GM143936-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** SARA JEAN WEAVER
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315746

## Citation

> US National Institutes of Health, RePORTER application 10315746, Structural insights into zinc homeostasis (1F32GM143936-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10315746. Licensed CC0.

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